Abstract
In response to Ca(2+) influx, a synapse needs to release neurotransmitters quickly while immediately preparing for repeat firing. How this harmonization is achieved is not known. In this study, we found that the Ca(2+) sensor synaptotagmin 1 orchestrates the membrane association/disassociation cycle of Rab3, which functions in activity-dependent recruitment of synaptic vesicles. In the absence of Ca(2+), synaptotagmin 1 binds to Rab3 GTPase activating protein (GAP) and inhibits the GTP hydrolysis of Rab3 protein. Rab3 GAP resides on synaptic vesicles, and synaptotagmin 1 is essential for the synaptic localization of Rab3 GAP. In the presence of Ca(2+), synaptotagmin 1 releases Rab3 GAP and promotes membrane disassociation of Rab3. Without synaptotagmin 1, the tight coupling between vesicle exocytosis and Rab3 membrane disassociation is disrupted. We uncovered the long-sought molecular apparatus linking vesicle exocytosis to Rab3 cycling and we also revealed the important function of synaptotagmin 1 in repetitive synaptic vesicle release.
Highlights
In nerve terminals, neurotransmitters are packaged into synaptic vesicles (SVs) and released by Ca2+-induced exocytosis (Sudhof, 2004)
Search for components involved in RAB-3/SV association In C. elegans motor neurons, RAB-3 fused with Green Fluorescent Protein (GFP) adopts a punctate pattern of localization along the length of the ventral and dorsal cords (Mahoney et al, 2006)
We revealed that SNT-1/synaptotagmin 1 functions as an onand-off switch to regulate Rab3 membrane association, facilitating repeated release
Summary
Neurotransmitters are packaged into synaptic vesicles (SVs) and released by Ca2+-induced exocytosis (Sudhof, 2004). Fast and precise neuronal reaction requires that SVs are clustered in front of the release site, the presynaptic active zone. The basic membrane fusion reaction is mediated by evolutionarily conserved soluble NSF attachment protein receptors (SNAREs) and related proteins like Munc and Munc (Weber et al, 1998; Sudhof, 2004; Brunger, 2005; Jahn and Scheller, 2006; Lang and Jahn, 2008; Jahn and Fasshauer, 2012). The Ca2+-sensing process that starts the SNARE engine is primarily carried out by the synaptotagmin family (Chapman, 2002; Jahn and Fasshauer, 2012). Through their C2 domains, synaptotagmins bind to Ca2+, triggering membrane fusion (Sudhof, 2004). SVs undergo endocytosis and recycling and are refilled with neurotransmitters for repeated rounds of release
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